Methylation of cytosines in CpG islands in the promoter region affects promoter activity and can down-regulate gene transcription. Because the promoter hypermethylation of genes in cancer cells is as significant as deletions or mutations, hypermethylation of key regulatory genes can play a significant role in transformation and tumor progression. Progression of transformed cells requires regulatory gene inactivation that promotes growth, dedifferentiation, invasion, and/or metastasis.
Transcription factors containing a basic helix-loop-helix (bHLH) motif regulate the expression of certain tissue-specific genes and have important roles in cell differentiation and embryonic developmental processes. DNA-binding activity of the bHLH proteins is dependent on formation of homo- and/or hetero-dimers. ID family proteins, which are distinct members of the helix-loop-helix (HLH) protein family, contain the HLH-dimerization domain but lack the DNA-binding basic domain. Consequently, ID proteins dominantly inhibit binding to DNA and transcriptional transactivation by forming heterodimers with bHLH proteins and modulate various key developmental processes. Currently, four known human ID proteins have been identified. Expression studies have shown that ID proteins play critical roles in early embryonic development. They are also involved in angiogenesis, lymphocyte development, cell cycle control, and cellular senescence. The involvement of ID proteins in neoplastic processes has been suggested. Increased ID1 and ID2 expression has been reported in various tumor types, including adenocarcinomas arising from the colon and pancreas. Transgene expression of ID1 and ID2 in mice has resulted in tumor formation in the intestinal epithelium and lymphoid organs, respectively. Expression of ID3 has been more variable; studies report both up-regulation and down-regulation in different tumor types.